Academic journal article Genetics

Variation in Genomic Recombination Rates among Heterogeneous Stock Mice

Academic journal article Genetics

Variation in Genomic Recombination Rates among Heterogeneous Stock Mice

Article excerpt

ABSTRACT

We used a large panel of pedigreed, genetically admixed house mice to study patterns of recombination rate variation in a leading mammalian model system. We found considerable inter-individual differences in genomic recombination rates and documented a significant heritable component to this variation. These findings point to clear variation in recombination rate among common laboratory strains, a result that carries important implications for genetic analysis in the house mouse.

THE rate of recombination-the amount of crossing over per unit DNA-is a key parameter governing the fidelity of meiosis. Recombination rates that are too high or too low frequently give rise to aneuploid gametes or prematurely arrest the meiotic cell cycle (Hassold and Hunt 2001). As a consequence, recombination rates should experience strong selective pressures to lie within the range defined by the demands of meiosis (Coop and Przeworski 2007). Nonetheless, classical genetic studies in Drosophila (Chinnici 1971; Kidwell 1972; Brooks and Marks 1986), crickets (Shaw 1972), flour beetles (Dewees 1975), and lima beans (Allard 1963) have shown that considerable inter-individual variation for recombination rate is present within populations. Recent studies examining the transmission of haplotypes in human pedigrees have corroborated these findings (Broman et al. 1998; Kong et al. 2002; Coop et al. 2008).

Here, we use a large panel of heterogeneous stock (HS) mice to study variation in genomic recombination rates in a genetic model system. These mice are genetically admixed, derived from an initial generation of pseudorandom mating among eight common inbred laboratory strains (DBA/2J, C3H/HeJ, AKR/J, A/J, BALB/cJ, CBA/J, C57BL/6J, and LP/J), followed by .50 generations of pseudorandom mating in subsequent hybrid cohorts (Mott et al. 2000; Demarest et al. 2001). The familial relationships among animals in recent generations were tracked to organize the mice into pedigrees. In total, this HS panel includes 2300 animals comprising 85 families, 8 of which span multiple generations. The remainder consists of nuclear families (sibships) that range from 1 to 34 sibs, with an average of 9.6 sibs (Valdar et al. 2006) (Table 1). Additional details on the derivation and history of these HS mice are provided elsewhere (see Mott et al. 2000; Demarest et al. 2001; Shifman et al. 2006).

With the exception of several founding individuals, most of these HS mice have been genotyped at 13,367 single nucleotide polymorphisms (SNPs) across the genome (available at http://gscan.well.ox.ac.uk/). Although the publicly available HS genotypes have passed data quality filters (Shifman et al. 2006), we took several additional measures to ensure the highest possible accuracy of base calls. First, data were cleansed of all non-Mendelian inheritances, and genotypes with quality scores <0.4 were removed. Genotypes that resulted in tight (<10 cM in sex-specific distance) double recombinants were also omitted because strong positive crossover interference in the mouse renders such closely spaced crossovers biologically very unlikely (Broman et al. 2002). A total of 10,195 SNPs (including 298 on the X chromosome) passed these additional quality control criteria; the results presented below consider only this subset of highly accurate (>99.98%) and complete (<0.01% missing) genotypes. The cleaned data are publicly available (at http://cgd.jax.org/mousemapconverter/).

We used the chrompic program within CRI-MAP (Lander andGreen 1987;Green et al. 1990) to estimate the number of recombination events in parental meioses. The algorithm implemented in chrompic first phases parent and offspring genotypes using a maximumlikelihood approach. Next, recombination events occurring in the parental germline are identified by comparing parent and offspring haplotypes across the genome (Green et al. 1990). For example, a haplotype that first copies from one maternal chromosome and then switches to copying from the other maternal chromosome signals a recombination event in the maternal germline. …

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